Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication

Circ Cardiovasc Genet. 2008 Oct;1(1):21-30. doi: 10.1161/CIRCGENETICS.108.773168.

Abstract

Background: Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.

Methods and results: We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein(Apo) A1, and ApoB. Genome-wide associations (P < 5 x 10(-8)) were found at the PCSK9 gene, the APOB gene, theLPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition,genome-wide associations with triglycerides at the GCKR gene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.

Conclusion: Genome-wide associations at the GCKR gene and near the SORT1 gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.

Keywords: GWAS; cardiovascular disease; lipid; lipoprotein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / genetics
  • Apolipoproteins B / blood
  • Apolipoproteins B / genetics
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / genetics
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / genetics
  • European Continental Ancestry Group / genetics*
  • Female
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease
  • Genome, Human / genetics
  • Genome-Wide Association Study*
  • Humans
  • Lipid Metabolism / genetics
  • Lipids / blood*
  • Lipids / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Reproducibility of Results
  • Triglycerides / blood
  • Triglycerides / genetics

Substances

  • Apolipoprotein A-I
  • Apolipoproteins B
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Lipids
  • Triglycerides